The first two decades of the past half-century marked the first successful treatment in a preventive mode of the most anciently recognized form of crystal-induced arthritis--gouty arthritis, by simply reducing the supersaturated concentrations of serum urate to the normal range by use of new drugs that became available. (Seegmiller, J E., "Conquest of Gouty Arthritis" in Landmark Advances in Rheumatology, ed. McCarty, D J (Amer. Rheum. Assn., Atlanta, Ga.) pp. 89-101 (1985)). It may well serve as a model for similar success with the above new and as yet unpublished finding. An important difference is that the elevated pyrophosphate was first found inside, instead of outside, the cells (Lust, G., et al. Arthritis Rheum (1976) 19:479-487). Inorganic pyrophosphate (PPi) serves a number of different biological functions. In bone and growth plate cartilage, extracellular inorganic PPi provides a critical source of phosphate (Pi) for the physiologic deposition of calcium phosphate crystals during bone mineralization (Ali, Y., "Calcification of Cartilage" in Cartilage: Structure, Function, Biochemistry, ed. Hall, BK (Academic, New York), pp. 343-378 (1983); Oyajobi, B O, et al., J Bone Miner Res (:1259-1266 (1944); Anderson, H C, Rhem Dis Clin North Am 14:303-319 (1988), and Rosen et al., Arthritis & Rheumatism, 40:7 (July 1997)).
Although PPi is required for the induction of calcification (Russell, R G, et al., Calcif Tissue Res. (1970) 6:183-196; Siegel, S A et al., (1983) J Biol Chem 258:8601-8607), an excess of free PPi in relation to Pi suppresses mineralization by inhibiting hydroxyapatite crystal nucleation from amorphous calcium phosphate (Ali, Y., "Calcification of Cartilage" in Cartilage: Structure, Function, Biochemistry, ed. Hall, BK (Academic, New York), pp. 343-378 (1983); Oyajobi, B O, et al., J Bone Miner Res (:1259-1266 (1944); Anderson, H C, Rhem Dis Clin North Am 14:303-319 (1988), and Rosen et al., Arthritis & Rheumatism, 40:7 (July 1997)). Chondrocytes in articular cartilage have the unique ability to constitutively elaborate extracellular PPi in large amounts (Rosenthal, A K et al. (1993) Arthritis Rheum. 36:539-542; Derfus, B A et al., Arthritis Rheum 35:231-240 (1992)), which helps to suppress mineralization of the avascular cartilage matrix (Poole, A R (1992) in Arthritis and Allied Conditions, eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 335-345).
PPi elaboration is governed by the balance between PPi formation and degradation (Rachow, J W and Ryan, L M (1988) Rheum Dis Clin North Am 14:289-302). PPi generation is a byproduct of many synthetic reactions in the cell (Rachow, J W and Ryan, L M (1988) Rheum Dis Clin North Am 14:289-302) and is a direct product of enzymes that have nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity. PPi degradation is affected by several inorganic pyrophosphatases, including alkaline phosphatase. (Rachow, J W and Ryan, L M (1988) Rheum Dis Clin North Am 14:289-302, Rasmussen, H. (1983) in The Metabolic Basis of Inherited Disease, eds. Stanbury, H., et al., (McGraw-Hill, New York), pp. 1497-1507).
Regulation of NTPPPH activity, and of other factors that modulate elaboration of extracellular PPi in cartilage and bone, appears critical not only to physiologic mineralization, but also to the development of certain disorders of pathologic mineralization (Anderson, H C, Rhem Dis Clin North Am 14:303-319 (1988). One example is a prevalent disease of the elderly known as idiopathic chondrocalcinosis. In this disease, the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in articular cartilage is strongly linked to substantial increases in NTPPPH activity and PPi concentration (Tenenbaum, J. et al., (1981) Arthritis Rheum 24:492-500; Ryan, L M and McCarty, D J (1992) in Arthritis and Allied Conditions, eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1835-1856; Jones, A C, et al., (1992) Semin Arthritis Rheum 22:188-202).
In addition, a 2-3-fold increase in intracellular PPi has been found in cartilage cells, fibroblasts, and lymphoblasts cultured from chondrocalcinosis patients (Lust, G. et al., (1976) Arthritis Rheum 19:479-487; Lust, G., et al., (1981) Science 214:809-810; Ryan, L M, et al. (1986) J Clin Invest 77:1689-1693). The capacity of CPPD crystals to activate an inflammatory response can promote acute and chronic inflammatory synovitis and cartilage degeneration (Ryan, L M and McCarty, D J (1992) in Arthritis and Allied Conditions, eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1835-1856; Terkeltaub, R. (1992) in Arthritis and Allied Conditions, eds. McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1819-1833). Moreover, the presence of CPPD crystal deposition commonly complicates prior articular injury and is an adverse prognostic factor in osteoarthritis (Ryan, L M and McCarty, D J (1992) in Arthritis and Allied Conditions, eds., McCarty, D J and Koopman, W J (Lea & Febiger, Philadelphia), pp. 1835-1856; Sokoloff, L. & Varma, A A (1988) Arthritis Rheum 31:750-756).
"Pseudogout" was the term first used to describe the clinical syndrome of acute gout-like arthritis associated with the presence of crystals of calcium pyrophosphate dihydrate in synovial fluid (McCarty, D J et al., I. Clinical aspects. Ann Intern Med 56:711 (1962). Also, see Seegmiller, J E, "Gout and Pyrophosphate Gout (Chondrocalcinosis,") in Principles of Geriatric Medicine and Gerontology, Third Edition, 1994, Hazzard, W., et al., eds., McGraw-Hill, Inc., pp. 987-994). Subsequent studies showed this gout-like presentation to be just one aspect of the far larger range of clinical presentations of patients showing radiologic evidence of a characteristic pattern of calcification within the joints, which is called "chondrocalcinosis" (Zitnan, D., and Sitaj, D., Cesk Radiol 14:27 (1960)) and more precisely designated as "calcium pyrophosphate dihydrate crystal deposition disease" (CPDD) (Ryan, L M, and McCarty, D J, "Calcium Pyrophosphate Crystal Deposition Disease: Pseudogout: Articular Chondrocalcinosis," in McCarty, D J (ed): Arthritis and Allied Conditions: A Textbook of Rheumatology, 10th ed., Philadelphia, Lea & Febiger, 1985, p. 1515). Since these multiple names for the same basic pathological process are confusing to both students and professionals, a subcommittee of the American College of Rheumatology has recommended the name "pyrophosphate gout" as being a more specific and simple designation for naming this disorder in a whole family of pathological states that would include apatite gout, cholesterol gout, and oxalate gout, with the prototype, urate gout, being referred to simply as "gout." (Simkin, P A, JAMA 260:1285 (1988)).
Pyrophosphate gout shows similarities to gouty arthritis in that it is a crystal-induced arthritis with intermittent acute attacks associated with appearance of crystals within phagocytes in the joint fluid and a consequent acute inflammatory reaction (Ryan, L M, and McCarty, D J, "Calcium Pyrophosphate Crystal Deposition Disease: Pseudogout: Articular Chondrocalcinosis," in McCarty, D J (ed): Arthritis and Allied Conditions: A Textbook of Rheumatology, 10th ed., Philadelphia, Lea & Febiger, 1985, p. 1515; McCarty, D J, et al, (1962), Ann Intern Med 56:711). The overall incidence of pyrophosphate gout increases markedly in later years of life. It is seldom seen in patients below age 50 except in familial forms of the disease. However, X-ray evidence of the disease has been found in some 44 percent of patients over age 84 and in 50 percent of patients in a nursing home over age 90 (Wilkins, E et al. Ann Rheum Dis (1983) 42:280-284).
Instead of needle-shaped crystals of monosodium urate monohydrate deposited in and about the joint as seen in gouty arthritis, the deposits of crystals in pyrophosphate gout consist of rhombic or broad-shaped crystals of calcium pyrophosphate dihydrate that are typically found as a punctate or lamellar layer in the midzone of the cartilage. This is most often seen on x-ray films of the knee in meniscal fibrocartilage, as well as in the articular cartilage of the knee, in the articular disk of the distal radioulnar joint of the wrists, and, less frequently, in and about other major joints (Resnick, D., JAMA (1979) 242:2440).
Several large pedigrees of hereditary pyrophosphate gout have been reported, most of which show evidence of a dominant pattern of inheritance (Seegmiller, J E, in Emery A., Rimoin, D (eds): The Principles and Practices of Medical Genetics, 2d ed. New York, Churchill Livingstone (1990), p. 1697; Van der Korst, J K and Gerard, J. Arthritis Rheum (1976) 19:405; Reginato, A J, Arthritis Rheum (1976) 19:395; McKusick, V.: Mendelian Inheritance in Man, 7th ed. (1986) The Johns Hopkins University Press). The close association of osteoarthritis and pyrophosphate gout (Wilkins, E et al. Ann Rheum Dis (1983) 42:280) has been recently confirmed by autopsy studies showing a frequency of concurrence of these diseases sixfold greater than would be expected from the chance association represented by the respective frequencies of both individual diseases in the population (Sokoloff, L, and Varma, A A, Arthritis Rheum (1988) 31:750). The discovery of modest elevations of pyrophosphate levels in synovial fluid of patients with more severe osteoarthritis suggests a possible metabolic link between the two diseases (Howell, D S, et al. Arthritis Rheum (1976) 19:488-494). Further evidence of such a link was found in chondrocytes cultured from normal, osteoarthritic and pyrophosphate gout (chondrocalcinosis) patients. The intracellular PPi was 2-fold over normal in the pyrophosphate gout patients and the osteoarthritis patients showed values intermediate between the two (Lust, G. et al. Arthritis Rheum (1976) 19:479-487). In unpublished work from the inventor's laboratory mononuclear cells isolated from peripheral blood also showed a significantly higher than normal concentration of intracellular PPi presented in Table 3 of this document.
Until the present invention, no rational approach was known for correction of the underlying metabolic abnormality responsible for calcium pyrophosphate crystal formation and the resulting development of disease (Seegmiller, J E, "Gout and Pyrophosphate Gout (Chondrocalcinosis," in Principles of Geriatric Medicine and Gerontology, Third Edition, 1994, Hazzard, W., et al., eds., McGraw-Hill, Inc., pp. 987-994).
This invention provides an unexpected use for an existing class of calcium blocking drugs, or calcium antagonists. During early clinical application of a new assay for pyrophosphate developed in the inventor's laboratory (Barshop, B A et al. Analyt Biochem (1991) 197:266-272), the inventors unexpectedly found that the calcium channel antagonists, nifedipine or diltiazem, widely used for management of hypertension, also lowers the intracellular concentration of pyrophosphate (PPi), and therefore should be useful for treatment of illnesses caused by the near 2-fold increase above normal of the intracellular PPi first found earlier by the inventor's laboratory in chondrocytes cultures from a patient with pyrophosphate gout (then called chondrocalcinosis) while the corresponding fibroblasts cultured from the same patient showed PPi values some 2.6 fold greater than the normals with less marked elevations found in patients with osteoarthritis (Lust, G. et al. Arthritis Rheum (1976) 19:479-487) calcium pyrophosphate crystal deposition, of pyrophosphate gout or less marked elevations of intracellular PPi we had found in patients with osteoarthritis.
Calcium antagonists are heterogeneous and fall into 3 major classes: the phenylalkylamines (verapamil), the dihydropyridines (nifedipine), and the benzothiazepines (diltiazem). Although Palmieri, et al, (Arth. & Rhem. 38:1646-1654 (1995) report dissolution of calcinosis in the cervical spine in a patient by long-term administration of diltiazem, this illness was designated as CREST syndrome, a more indolent and less severe sub-type of progressive systemic sclerosis (scleroderma). With its limited cutaneous involvement, skin thickening and scarring of the skin is most often limited to the face and/or hands. This variant has been designated CREST, an abbreviation for its components (calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, and telangectasia) (Medsger, T A, "Systemic Sclerosis (Scleroderma)" in Internal Medicine, ed. Stein, J H (Mosby-Year Book, Inc., Baltimore), pp. 2443-24 (1949)). Since specific autoantibodies are also found in most cases and the calcinosis involves the extracellular deposition of calcium phosphate nodules, CREST syndrome is quite unrelated to pyrophosphate gout in either clinical or biochemical features. Therefore, this invention provides the first rational use of calcium antagonists for rational treatment of illnesses caused by calcium pyrophosphate crystal deposition.